This invention relates to a process for the preparation of (2R)-2-propyloctanoic acid. More particularly, this invention relates to a process for the preparation of (2R)-2-propyloctanoic acid, which is characterized by subjecting (2S)-2-(2-propynyl)octanoic acid or (2S)-2-(2-propenyl)octanoic acid to reduction using platinum on carbon as a catalyst.
The optically active (2R)-2-propyloctanoic acid (hereinafter, it is referred to as a present compound) prepared by the present process is useful for the pharmaceuticals.
For the pharmaceutical, an optical purity of the object compound is important. On an activity of optical isomers, there are some reports on pharmaceutical that one of the isomers is superior to the other on a main action, or one does not have toxicity but the other has severe toxicity. A slight amount of optical impurities causes a dangerous unexpected side effect.
Accordingly, for development of safe pharmaceuticals, it is required to use optically active compound instead of racemate, and an optical purity is required to be almost 100%.
The present compound of the present invention is useful for pharmaceuticals. For example, the racemate of (2R)-2-propyloctanoic acid is described in the Example 7(33) of JP-A-7-316092 (EP 632008) as an agent for treating or preventing neurodegerative diseases derived from functional abnormality of astrocytes.
As a result of further study, it was found that the optically active R-configuration compound has strong activities, and lower toxicity. Accordingly, various studies have been conducted to find a process for obtaining the optically active R-configuration compound effectively.
The process for the preparation of (2R)-2-propyloctanoic acid was described, for example, in JP-A-8-291106, wherein an optically active salt was obtained by optical resolution of racemic 2-(2-propynyl)octanoic acid with optically active amine, and the resulting salt was treated with an acid to afford optically active (2S)-2-(2-propynyl)octanoic acid, and then it was subjected to reduction. Besides, in WO 99/58513, (2R)-2-propyloctanoic acid was prepared by subjecting2S-(2-propenyl)octanoic acid or 2S-(2-propynyl)octanoic acid to reduction.
In the above specifications, it was described that a preferable reduction was a catalytic reduction method, more particularly, it may be carried out in an organic solvent, by using a catalyst (e.g. palladium on carbon, palladium, platinum, platinum oxide, nickel) under an atmosphere of hydrogen at 0-60xc2x0 C. The example using palladium on carbon was described in both specifications.
However, it was proved that a few percentage of S-configuration compound would be inevitably formed as a by-product through isomerization during the reduction under this condition.
Energetic investigations have been carried out in order to solve the problem of a production of S-configuration compound as by-product. Accordingly the present inventors have found that there occurs substantially no isomerization and present compound having high optical purity can be obtained by using platinum on carbon instead of palladium on carbon and completed the present invention. That is, by the process of the present invention, there occured almost no isomerization, and highly pure and safe medicaments can be supplied.
The fact that by using platinum on carbon, there happened substantially no isomerization and present compound having high optical purity can be obtained was not known until now, and it is proved for the first time at this study.
(2S)-2-(2-propynyl)octanoic acid and (2S)-2-(2-propenyl)octanoic acid used as a starting material were known compounds, for example, described in WO 99/58513.
In the present invention, the hydrogenation of the starting material may be carried out in an organic solvent (e.g. ethyl acetate, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, biphenyl ether, methyl alcohol, ethyl alcohol, isopropyl alcohol, benzene, toluene, xylene, HMPA, dimethylformamide, dimethylimidazolidine, mixture thereof), by using a platinum on carbon under an atmosphere of hydrogen at 0-60xc2x0 C.
Platinum on carbon used in the present invention is commercially available.
A preferable amount for use is 0.1-20 wt %, more preferably 0.1-10 wt % based on the material.
According to the process of the present invention, there occurs no isomerization and (2R)-2-propyloctanoic acid having high optical purity can be obtained compared to conventional process (wherein, palladium on carbon is used as catalyst).
That is, there happened partial isomerization by the conventional process and the optical purity was decreased, but by the process of the present invention, there occurs substantially no isomerization and present compound having high purity can be obtained.
The following table shows optical purity of the present compound, which prepared by the process of the present invention and a conventional process (comparative example 1 and 2 as described later).
The above table shows that optical purity of the present compound prepared by the process of present invention keeps high optical purity, but the optical purity of the compound prepared by the process of comparative example is remarkably decreased.
Specifically, optical purity of the present compound prepared by the process of comparative examples is decreased by 3.8% and 2.8% on the basis of the starting material, but the optical purity of the present compound is decreased by only 0.4% and 0.6%, and the optical purity of the present compound remains high.
As mentioned above, keeping the content of the by-product as low as possible has a large significance for pharmaceuticals. From this view point, it is an important achievement that an amount of by-product is decreased and optical purity of the present compound remains high. It was not expected at all that these effects could be obtained by the present invention.
Accordingly, by the process of the present invention, the present compound can be obtained without isomerization, and the present compound has a high optical purity, therefore it is considered that the present process is outstanding.